There are more than 80 types of human papillomavirus (HPV), many of which have been associated with pathologies ranging from benign proliferative warts to malignant carcinomas of the cervix (for review, see McMurray et al., Int. J. Exp. Pathol. 82(1): 15-33 (2001)). HPV types 6 and 11 are termed “low-risk” and are the HPV types which are most commonly associated with benign warts, nonmalignant condyloma acuminata and/or low-grade dysplasia of the genital or respiratory mucosa. Approximately 90% of genital warts are caused by these two HPV types. In contrast, HPV16 and HPV18 are termed “high-risk” HPV types because they are most frequently associated with in situ and invasive carcinomas of the cervix, vagina, vulva and anal canal. More than 70% of cervical carcinomas are caused by infections with HPV16 and HPV18. Together with the less prevalent oncogenic types HPV 31, -33, -45, -52 and -58, these types account for greater than 90% of cervical cancer (Schiffman et al., J. Natl. Cancer Inst. 85(12): 958-64 (1993)). Cervical cancer is the second most prevalent cause of cancer deaths in women worldwide.
Papillomaviruses are small (50-60 nm), nonenveloped, icosahedral DNA viruses that encode up to eight early (E1- E7) and two late (L1-L2) genes. The L1 protein is the major capsid protein and has a molecular weight of 55-60 kDa. Expression of the L1 protein or a combination of the L1 and L2 proteins in yeast, insect cells, mammalian cells or bacteria leads to self-assembly of virus-like particles (VLPs) (for review, see Schiller and Roden, in Papillomavirus Reviews Current Research on Papillomaviruses; Lacey, ed. Leeds, UK: Leeds Medical Information, pp 101-12 (1996)). VLPs are morphologically similar to authentic virions and are capable of inducing high titres of neutralizing antibodies upon administration into animals or humans. Because VLPs do not contain the potentially oncogenic viral genome, they present a safe alternative to the use of live virus in HPV vaccine development (for review, see Schiller and Hidesheim, J. Clin. Virol. 19: 67-74 (2000)). For this reason, the L1 and L2 genes have been identified as immunological targets for the development of prophylactic and therapeutic vaccines for HPV infection and disease.
VLP-based vaccines have proven to be effective at inducing immune responses in human patients vaccinated with bivalent HPV 16 and 18 (Harper et al. Lancet 364(9447): 1757-65 (2004)) and quadrivalent HPV 6, 11, 16, and 18 VLP-based vaccines (Villa et al. Vaccine 24: 5571-5583 (2006)). However, it is a common goal of vaccine development to augment the immune response to the desired antigen to induce long lasting protective immunity.
Co-administration of vaccines with compounds that can enhance the immune response against the antigen of interest, known as adjuvants, has been extensively studied. In addition to increasing the immune response against the antigen of interest, some adjuvants may be used to decrease the amount of antigen necessary to provoke the desired immune response or decrease the number of injections needed in a clinical regimen to induce a durable immune response and provide protection from disease.
Aluminum-based compounds were determined to possess adjuvant activity over 60 years ago (for review, see Lindblad, E. B. Immunol. and Cell Biol. 82: 497-505 (2004); Baylor et al. Vaccine 20: S18-S23 (2002)). Aluminum adjuvants are generally regarded as safe when used at appropriate dosages. Many have been approved for administration into humans by regulatory agencies worldwide.
While the mechanism of action of aluminum adjuvants is not completely understood, it is generally thought that for optimal immunostimulating effect, the targeted antigen should be adsorbed onto the aluminum in a vaccine preparation (see Lindblad, supra). When formulated in this manner, aluminum adjuvants are able to induce potent antibody (TH2) responses against many antigens; but rarely stimulate cellular (TH1) immune responses. With regards to HPV, it has been shown that an HPV 6, 11, 16 and 18 L1 VLP-based vaccine in which the VLPs were adsorbed to an aluminum adjuvant produced a significantly stronger immune response in rhesus macaques than the response resulting from a corresponding L1 VLP vaccine lacking aluminum (Ruiz et al., Journal of Immune Based Therapies and Vaccines 3(1): 2 (2005)). It is important to note that while significantly higher antibody titers resulted from the aluminum-adjuvanted vaccine relative to VLPs alone, the immune response was not qualitatively different as both adjuvanted and non-adjuvanted vaccines produced similar isotype profiles.
In order to develop prophylactic HPV vaccines with long-term efficacy, it would be advantageous to achieve higher magnitude immune responses comprising strong humoral as well as cellular immune responses. It would also be beneficial to develop a VLP-based vaccine that produces an immune response to HPV L1 this is sufficiently enhanced to allow a reduced number of vaccine injections relative to current prophylactic clinical schedules.